The present invention generally relates to benzothiazole compounds useful as adenosine receptor ligands. Specifically, the present invention relates to compounds having good affinity to the A2A-receptor and a high selectivity to the A1- and A3 receptors.
Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzym A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
The receptores for adenosine have been classified as A1, A2A, A2B and A3 receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine initiates signal transduction mechanism. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtyps has been classically characterised by the adenylate cyclase effector system, which utilises CAMP as a second messenger. The A1 and A3 receptors, coupled with Gi proteins inhibit adenylate cyclase, leading to a decrease in cellular CAMP levels, while A2A and A2B receptors couple to Gs proteins and activate adenylate cyclase, leading to an increase in cellular CAMP levels. It is known that the A1 receptor system include the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A3 subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and so activates calcium ion channels.
The A1 receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A2A receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A2B receptor (332 amino acids) was cloned from human and mouse with 45% homology of human A2B with human A1 and A2A receptors. The A3 receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.
The A1 and A2A receptor subtypes are proposed to play complementary roles in adenosine""s regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A1) or increase the oxygen supply (A2A) and so reinstate the balance of energy supply: demand within the tissue. The actions of both subtyps is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischaemia, hypotension and seizure activity.
Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A3 receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A3 receptor plays a role in mediating asthmatic attacks and other allergic responses.
Adenosine is a neuromodulator, able to modulate many aspects of physiological brain function. Endogenous adenosine, a central link between energy metabolism and neuronal activity, varies according to behavioural state and (patho)physiological conditions. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia, and/or excessive neuronial activity), adenosine provides a powerful protective fedback mechanism. Interacting with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases such as epilepsy, sleep, movement disorders (Parkinson or Huntington""s disease), Alzheimer""s disease, depression, schizophrenia, or addiction. An increase in neurotransmitter release follows traumas such as hypoxia, ischaemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A1 agonists which mimic the central inhibitory effects of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A2a antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer""s disease, and of neurodegenerative disorders, e.g. stroke. Adenosine A2b receptor antagonists modulate the activity of striatal GABAergic neurons and regulate smooth and well-coordinated movements, thus offering a potential therapy for Parkinsonian symptoms. Adenosine is also implicated in a number of physiological processes involved in sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Drugs acting, at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants, and to treat drug abuse. They may also be used in the treatment of ADHD (attention deficit hyper-activity disorder).
An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischaemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). By acting at the A1 receptor, adenosine A1 agonists may protect against the injury caused by myocardial ischemia and reperfusion. The modulating, influence of A2a receptors on adrenergic function may have implications for a variety of disorders such as coronary artery disease and heart failure. A2a antagonists may be of therapeutic benefit in situations in which an enhanced antiadrenergic response is desirable, such as during acute myocardial ischemia. Selective antagonists at A2a receptors may also enhance the effectiveness of adenosine in terminating supraventricula arrhytmias.
Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds which antagonise the renal affects of adenosine have potential as renal protective agents. Furthermore, adenosine A3 and/or A2B antagonists may be useful in the treatment of asthma and other allergic responses or and in the treament of diabetes mellitus and obesity.
Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:
Bioorganic and Medicinal Chemistry, 6, (1998), 619-641,
Bioorganic and Medicinal Chemistry, 6, (1998), 707-719,
J. Med. Chem., (1998), 41, 2835-2845,
J. Med. Chem., (1998), 41, 3186-3201,
J. Med. Chem., (1998), 41, 2126-2133,
J. Med. Chem., (1999), 42, 706-721,
J. Med. Chem., (1996), 39, 1164-1171,
Arch. Pharm. Med. Chem., 332, 39-41, (1999),
Am. J. Physiol., 276, H1113-1116, (1999) or
Naunyn Schmied, Arch. Pharmacol. 362, 375-381, (2000).
The present invention relates to compounds of the formula 
wherein R1, A and R are as defined herewithin.
The present invention generally relates to compounds of formula IA and IB per se, the use of compounds of formula IA and IB and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases, related to the adenosine A2 receptor. The present invention further relates to the manufacture of compounds of formula IA and IB, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula IA and IB in the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, drug addiction, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or against asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents for disorders such as coronary artery disease and heart failure. The most preferred indications in accordance with the present invention are those, which base on the A2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of Alzheimer""s disease, certain depressive disorders, drug addiction, neuroprotection and Parkinson""s disease as well as ADHD.
The present invention relates to compounds of the formula 
wherein
R1 is phenyl, piperidin-1-yl or morpholinyl;
A is xe2x80x94Oxe2x80x94 and
R is xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94O-lower alkyl, lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2, xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)n-2-oxo-pyrrolidinyl or C4-6-cycloalkyl;
Rxe2x80x3 is independently selected from hydrogen and lower alkyl; and
n is 1 or 2; or
A is xe2x80x94N(Rxe2x80x2)xe2x80x94 and
R is lower alkyl, C4-6-cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)n-piperidinyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)n-morpholinyl, or xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2;
Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen and lower alkyl; and
n is 1 or 2; or
A is xe2x80x94CH2xe2x80x94 and
R is xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94N(Rxe2x80x3)2, S-lower alkyl, or is acetidinyl, pyrrolidinyl or piperidinyl, which are optionally substituted by hydroxy or lower alkoxy or is morpholinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C4-6-cycloalkyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)O-lower alkyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)OH, -2-oxo-pyrrolidinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94C(O)O-lower alkyl, xe2x80x94O(CH2)mxe2x80x94O-lower alkyl or alkoxy;
Rxe2x80x3 is independently selected from hydrogen and lower alkyl; and
m is 1, 2 or 3;
or
A is xe2x80x94Sxe2x80x94 and
R is lower alkyl;
or
Axe2x80x94R are together
-piperazinyl, substituted by lower alkyl, xe2x80x94C(O)-lower alkyl or an oxo group, or is piperidinyl, substituted by lower alkoxy or hydroxy, or is morpholinyl, substituted by lower alkyl, or is xe2x80x94C4-6-cycloalkyl, -azetidin-1-yl, optionally substituted by hydroxy or lower alkoxy, thiomorpholine-1,1-dioxo, -tetrahydopyran or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl;
and pharmaceutically acceptable acid addition salts thereof.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a saturated straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 4-6 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues is as defined above, and which is attached via an oxygen atom.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulphonic acid and the like.
Preferred compound of the present application are compounds of formula IA, wherein R1 is morpholinyl and A is xe2x80x94Oxe2x80x94. Particularly preferred are those compounds, wherein R is cycloalkyl, xe2x80x94(CH2)nxe2x80x94NHC(O)CH3, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2,xe2x80x94(CH2)nxe2x80x94O-lower alkyl or lower alkyl, for example the following compounds:
2-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-ethoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-isopropoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-cyclohexyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-cyclopentyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(2-dimethylamino-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide or
2-(2-acetylamino-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide.
Further preferred are compounds of formula IA, wherein R1 is morpholinyl, A is xe2x80x94Oxe2x80x94 and R is xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)n-morpholinyl or xe2x80x94(CH2)n-2-oxo-pyrrolidinyl, for example the following compounds:
2-benzyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(pyridin-2-ylmethoxy)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy)-isonicotinamide or
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethoxy)-isonicotinamide.
Further preferred are compounds of formula IA, wherein R1 is morpholinyl, A is xe2x80x94NRxe2x80x2xe2x80x94 and R is xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)n-piperidinyl, xe2x80x94(CH2)n-phenyl or xe2x80x94(CH2)n-morpholidinyl, for example the following compounds:
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino]-isonicotinamide,
N-(4-methoxy-7- morpholin-4-yl-benzothiazol-2-yl)-2-(2-pyridin-2-yl-ethylamino)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-1 (pyridin-2-ylmethyl)-amino]-isonicotinamide,
2-[ethyl-(2-pyridin-2-yl-ethyl)-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-morpholin-4-yl-ethylamino)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-piperidin-1-yl-ethyl)-amino]-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-piperidin-1-yl-ethylamino)-isonicotinamide,
2-benzylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(benzyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(methyl-phenethyl-amino)-isonicotinamide or
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-phenethylamino-isonicotinamide.
Further preferred are compounds of formula IA, wherein R1 is morpholinyl, A is xe2x80x94NRxe2x80x2xe2x80x94 and R is lower alkyl, cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2 or xe2x80x94(CH2)nxe2x80x94NRxe2x80x3xe2x80x94C(O)-lower alkyl, for example the following, compounds:
2-[(2-methoxy-ethyl)-methyl-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(2-methoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-[ethyl-(2-methoxy-ethyl)-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(2-ethoxy-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(2-acetylamino-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-cyclohexcylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-cyclopentylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-cyclobutylamino-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(2-dimethylamino-ethylamino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-propylamino-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(methyl-propyl-amino)-isonicotinamide,
2-(cyclohexyl-methyl-amino)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide or
2-[(2-dimethylamino-ethyl)-methyl-amino]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide.
Further preferred are compounds of formula IA, wherein R1 is morpholinyl, A is xe2x80x94CH2xe2x80x94 and R is xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94O-lower alkyl, S-lower alkyl, xe2x80x94N(Rxe2x80x3)2, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mn-cycloalkyl or xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)O-lower alkyl, for example the following compounds:
2-[(2-methoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-[(2-ethoxy-ethylamino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-[(butyl-methyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-butylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-diethylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide,
2-ethylaminomethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-[(cyclopropylmethyl-amino)-methyl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
4-{[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-pyridin-2-yl-methyl]-amino}-butyric acid tert-butyl ester,
[4-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-carbamoyl)-pyridin-2-ylmethyl]-methyl-carbamic acid methyl ester,
2-ethylsulfanylmethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-{[(2-ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-Ethylsulfanylmethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-{[(2-Ethoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Preferred are further compounds of formula IA, wherein R1 is morpholinyl, A is xe2x80x94CH2xe2x80x94 and R is pyrrolidinyl, -2-oxo-pyrrolidinyl, piperidinyl, which is optionally substituted by lower alkoxy or hydroxy, or is morpholinyl or alkoxy, for example the following compounds:
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-pyrrolidin-1-ylmethyl-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(2-oxo-pyrrolidin-1-yl-methyl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-1-ylmethyl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-piperidin-1-ylmethyl-isonicotinamide,
2-(4-hydroxy-piperidin-1-ylmethyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-morpholin-4-ylmethyl-isonicotinamide,
2-methoxymethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide or
2-(4-hydroxy-piperidin-1-yl-methyl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide
Preferred compound of the present application are compounds of formula IA, wherein R1 is morpholinyl and A is xe2x80x94Sxe2x80x94, for example the following compounds:
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylsulfanyl-isonicotinamide or
2-ethylsulfanyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide.
Preferred compound of the present application are compounds of formula IA, wherein R1 is morpholinyl and Axe2x80x94R are together -piperazinyl, substituted by lower alkyl, xe2x80x94C(O)-lower alkyl or an oxo group, or is piperidinyl, substituted by lower alkoxy or hydroxy, or is morpholinyl, substituted by lower alkyl, or is -cyclohexyl, -azetidin-1-yl, which is optionally substituted by hydroxy or lower alkoxy, or is -tetrahydopyran, or is 1,1-dioxo-thiomorpholinyl or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, for example the following compounds:
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-1-yl)-isonicotinamide,
2-(4-acetyl-piperazin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methyl-3-oxo-piperazin-1-yl)-isonicotinamide,
2-(4-ethyl-3-oxo-piperazin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-[(2R,6S)-2,6-dimethyl-morpholin-4-yl]-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-cyclohexcyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-azetidin-1-yl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(4-methoxy-piperidin-1-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(3-methoxy-piperidin-1-yl)-isonicotinamide,
2-(3-hydroxy-piperidin-1-yl)-N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-(tetrahydro-pyran-4-yl)-isonicotinamide,
N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-{(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl}-isonicotinamide,
2-(1,1-dioxo-1l6-thiomorpholin-4-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(3-hydroxy-azetidin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide,
2-(3-methoxy-azetidin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide or
2-(3-ethoxy-azetidin-1-yl)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide.
Preferred compound of the present application are compounds of formula IA, wherein R1 is piperidinyl and Axe2x80x94R are together piperazinyl, substituted by lower alkyl, for example the following compound
N-(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-2-(4-methyl-piperazin-1-yl)-isonicotinamide.
Preferred compound of the present application are compounds of formula IA, wherein R1 is phenyl, A is xe2x80x94Oxe2x80x94 and R is lower alkyl, for example the following compound 2-methoxy-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-isonicotinamide.
Preferred are further compounds of formula IA, wherein R1 is piperidinyl. Especially preferred are those compounds, wherein A is xe2x80x94CH2xe2x80x94 and R is pyrrolidinyl or morpholidinyl, for example the following compounds:
N-(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-2-pyrrolidin-1-yl-methyl-isonicotinamide or
N-(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-2-morpholin-4-yl-methyl-isonicotinamide.
Compounds of formula IB are also preferred, for example those, wherein R1 is morpholinyl, A is xe2x80x94Oxe2x80x94 and R is lower alkyl, xe2x80x94(CH2)2xe2x80x94O-lower alkyl or cycloalkyl, for example
6-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide,
6-isopropoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide,
6-(2-methoxy-ethoxy)-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide or
6-cyclohexyloxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide.
The present compounds of formulas IA and I-B and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which processes comprise
a) reacting a compound of formula 
with a compound of formula
Hxe2x80x94Axe2x80x94Rxe2x80x83xe2x80x83(5)
in the presence of a base
to a compound of formula 
wherein R is xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94O-lower alkyl, lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2, xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)n-2-oxo-pyrrolidinyl or C4-6-cycloalkyl, Y is chloro or bromo, A is O or S, and n is 1 or 2;
b) reacting a compound of formula 
with a compound of formula
HNRRxe2x80x2xe2x80x83xe2x80x83(6)
to a compound of formula 
wherein R is lower alkyl, C4-6-cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl)-(CH2)n-pyridinyl, xe2x80x94(CH2)n-piperidinyl, (CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)n-morpholinyl or xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2 or R and Rxe2x80x2 form together with the N atom the following groups: piperazinyl, optionally substituted by lower alkyl, C(O)-lower alkyl or an oxo group, piperidinyl, optionally substituted by lower alkoxy or hydroxy, morpholinyl, optionally substituted by lower alkyl, azetidin-1-yl, optionally substituted by hydroxy or lower alkoxy, or thiomorpholine-1,1-dioxo or 2-oxa-bicyclo[2.21]hept-5-yl, Rxe2x80x2 and Rxe2x80x3 are independently from each other hydrogen or lower alkyl, Y is chloro or bromo and n is 1 or 2; or
c) reacting a compound of formula 
with a compound of formula
Hxe2x80x94Rxe2x80x83xe2x80x83(9)
to a compound of formula 
wherein R is xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94N(Rxe2x80x3)2, xe2x80x94S-lower alkyl or is acetidinyl, pyrrolidinyl or piperidinyl, which are optionally substituted by hydroxy or lower alkoxy or is morpholinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C4-6-cycloalkyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)O-lower alkyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)OH, -2-oxo-pyrrolidinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94C(O)O-lower alkyl, xe2x80x94O(CH2)mxe2x80x94O-lower alkyl or alkoxy, Rxe2x80x3 is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, or
d) reacting a compound of formula 
with a compound of formula
Hxe2x80x94Oxe2x80x94Rxe2x80x83xe2x80x83(5)
to give a compound of formula 
wherein R is xe2x80x94(CH2)mxe2x80x94O-lower alkyl or is lower alkyl and m is 1, 2 or 3, or
e) reacting a compound of formula 
with a compound of formula
Bu3Snxe2x80x94Axe2x80x2xe2x80x94R/cat or with B(OH)2xe2x80x94Axe2x80x2xe2x80x94R/cat
to a compound of formula 
wherein Axe2x80x2xe2x80x94R are together C4-6-cycloalkenyl or dihydopyran and Y is bromo, and then reacting a compound of formula IA4 or IB4 with hydrogen and a catalyst to give a compound of formula 
wherein Axe2x80x94R are together C4-6-cycloalkyl or tetrahydropyran, and
if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
The compounds of formulae IA and IB may be prepared in accordance with process variants a) to e) and with the following schemes 1 to 10.
One method of preparation of compounds of formula IA1 or IB1, wherein A is oxygen or sulfur, is from 2-chloro- or 2-bromo-isonicotinamide intermediates of formula (4A) or from 2-chloro- or 2-bromo-nicotinamide intermediates of formula (4B), the preparation of which is shown in reaction schemes 1 and 2 below. 
wherein R is xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94O-lower alkyl, lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2, xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)n-2-oxo-pyrrolidinyl or C4-6-cycloalkyl, A is O or S, and n is 1 or 2.
HATU is O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate. 
wherein R is xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94O-lower alkyl, lower alkyl, xe2x80x94(CH2)n-morpholinyl, xe2x80x94(CH2)n-phenyl) xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)n, xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94(CH2)n-2-oxo-pyrrolidinyl or C4-6-cycloalkyl, A is O or S, and n is 1 or 2.
HATU is O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate.
The starting 2-chloroisonicotinic acid or 2-bromoisonicotinic acid of formula (1A) or 2-chloronicotinic acid or 2-bromonicotinic acid of formula (IB) may be obtained commercially, for example from Maybridge Chemicals, or may be prepared according to methods well known in the art.
The 2-haloisonicotinic acid of formula (1A) or 2-halonicotinic acid of formula (IB) may be converted to the corresponding acyl halide derivative of formula (2A) or (2B) by reacting a compound of formula (1A) or (1B) with an excess of a halogenating agent, such as oxalyl chloride or oxalyl bromide, or thionyl chloride or thionyl bromide, using a catalyst such as N,N-dimethylformamide or pyridine, in an organic solvent, prefereably dichloromethane or dichloroethane, at room temperature for about 2-16 hours, preferably 16 hours. The product of formula (2) is isolated by conventional means, and preferably reacted in the next step without further purification.
The starting 2-amino-benzothiazole compounds of formula (3) may be prepared according to methods disclosed in EP 00113219.0.
The compounds of formula (4A) or (4B) are prepared by treating the 2-amino-benzothiazole compounds of formula (3) with a slight excess of the acyl halide compounds of formula (2A) or (2B) in a non-protic organic solvent, preferably a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine or triethylamine, at room temperature for 2-24 hours, preferably 24 hours. The product of formula (4A) or (4B) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
The compounds of formula (4A) or (4B) may also be prepared directly from compounds of formula (2A) or (2B). In this method, the compound of formula (2A) or 2(B) is treated with a stoichiometric equivalent of a peptide-coupling reagent, preferably O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine, at room temperature for 30-90 minutes. This mixture is then treated with a 2-amino-benzothiazole compound of formula (3) in a solvent mixture, preferably a mixture of tetrahydrofuran, dioxane and N,N-dimethylformamide, at room temperature for 16-24 hours, preferably 24 hours. The product of formula (4) is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
One method of preparation of compounds of formula IA1 or IB1, is by treatment of a compound of formula (4A) or (4B) with an excess of an appropriate alcohol or thiol of formula (5), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or thiol, or an aromatic alcohol or thiol, in each case used together with a metal-hydride base, preferably sodium hydride or potassium hydride. These reactions may be carried out in an ethereal solvent such as such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably dioxane, optionally containing a co-solvent such as N,N-dimethylformamide, at a temperature between room temperature and the reflux temperature of the solvent, preferably about 100xc2x0 C., for 2-72 hours, preferably 16 hours. The product of Formula I, where A is oxygen or sulfur, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
One method of preparation of compounds of formula IA1 and IB1 is from 2-bromoisonicotinamide intermediates of formula (4A) or from 2-chloro- or 2-bromonicotinamide intermediates of formula (4B), as shown in reaction schemes 3 and 4 below. 
R is lower alkyl, C4-6-cycloalkyl, xe2x80x94(CH2)nxe2x80x94O-lower alkyl, xe2x80x94(CH2)n-pyridinyl, xe2x80x94(CH2)n-piperidinyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)n-morpholinyl or xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2 or R and Rxe2x80x2 form together with the N atom the following groups: piperazinyl, optionally substituted by lower alkyl, C(O)-lower alkyl or an oxo group, piperidinyl, optionally substituted by lower alkoxy or hydroxy, morpholinyl, optionally substituted by lower alkyl, azetidin-1-yl, optionally substituted by hydroxy or lower alkoxy, or thiomorpholine-1,1-dioxo or 2-oxa-bicyclo[2.21]hept-5-yl. Rxe2x80x2 and Rxe2x80x3 are independently from each other hydrogen or lower alkyl, Y is bromo, Rxe2x80x2 and Rxe2x80x3 are independently from each other hydrogen or lower alkyl and n is 1 or 2. 
R is lower alkyl, C4-6-cycloalkyl, xe2x80x94(CH2)n-lower alkyl, xe2x80x94(CH)n-pyridinyl, xe2x80x94(CH2)n-piperidinyl, xe2x80x94(CH2)n-phenyl, xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)xe2x80x94C(O)-lower alkyl, xe2x80x94(CH2)n-morpholinyl or xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x3)2 or R and Rxe2x80x2 form together with the N atom the following groups: piperazinyl, optionally substituted by lower alkyl, C(O)-lower alkyl or an oxo group, piperidinyl, optionally substituted by lower alkoxy or hydroxy, morpholinyl, optionally substituted by lower alkyl, azetidin-1-yl, optionally substituted by hydroxy or lower alkoxy, or thiomorpholine-1,1-dioxo or 2-oxa-bicyclo[2.2 1]hept-5-yl, Rxe2x80x2 and Rxe2x80x3 are independently from each other hydrogen or lower alkyl, Y is chloro or bromo, Rxe2x80x2 and Rxe2x80x3 are independently from each other hydrogen or lower alkyl and n is 1 or 2.
To prepare the compounds of formula IA2 or IB2, the 2-bromo-isonicotinamide intermediate of formula (4A) or the 2-chloro- or 2-bromo-nicotinamide intermediate of formula (4B) is treated with a large excess of an appropriate amine of formula (6), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic amine or an aromatic amine, in each case used together with a metal carbonate base, preferably cesium carbonate. These reactions may be carried out in the absence of added solvent, or optionally in the presence of a solvent such as N,N-dimethylformamide or N-methylpyrrolidone, at an elevated temperature, preferably about 140xc2x0 C., for 2-48 hours, preferably 24 hours. The product of formula IA2 or IB2, where A is nitrogen, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
One method of preparation of compounds of formula IA or IB, wherein A is CH2, is from 2-chloromethyl-isonicotinamide intermediates of formula (4A1) or from 2-chloromethyl-nicotinamide intermediates of formula (4B1), as shown in reaction scheme 5 an 6 below. 
wherein R in this scheme for compounds of formula IA3-1 is xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94N(Rxe2x80x3)2, xe2x80x94S-lower alkyl or is acetidinyl, pyrrolidinyl or piperidinyl, which are optionally substituted by hydroxy or lower alkoxy, or is morpholinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C4-6-cycloalkyl, N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)O-lower alkyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)OH, -2-oxo-pyrrolidinyl or xe2x80x94N(Rxe2x80x3)xe2x80x94C(O)O-lower alkyl, Rxe2x80x3 is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, and R in this scheme for compounds of formula IA3-2 is xe2x80x94(CH2)mxe2x80x94O-lower alkyl or alkyl; 
wherein R in this scheme for compounds of formula IB3-1 is xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94N(Rxe2x80x3)2, xe2x80x94S-lower alkyl or is acetidinyl, pyrrolidinyl or piperidinyl, which are optionally substituted by hydroxy or lower alkoxy, or is morpholinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C4-6-cycloalkyl, N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)O-lower alkyl, xe2x80x94N(Rxe2x80x3)xe2x80x94(CH2)mxe2x80x94C(O)OH, -2-oxo-pyrrolidiinyl, xe2x80x94N(Rxe2x80x3)xe2x80x94C(O)O-lower alkyl, Rxe2x80x3 is independently from each other hydrogen or lower alkyl and m is 1, 2 or 3, and R in this scheme for compounds of formula IB3-2 is xe2x80x94(CH2)mxe2x80x94O-lower alkyl or alkyl, Rxe2x80x3 is hydrogen or lower alkyl, and m is 1, 2 or 3.
One method of preparation of compounds of formulae IA3-1 or IA3-2 and IB3-1 or IB3-2 is from the appropriately substituted benzothiazol-2-yl-amine (3) and 2-chloromethyl-isonicotinoyl chloride (4A1) or 2-chloromethyl-nicotinoyl chloride (4B1) as shown in reaction schemes 7 and 8 below. 
One method of preparation of compounds of formula IA3-1, IA3-2, IB3-1 or IB3-2 is by treatment of a compound of formula (4A1) or (4B1) with an excess of an appropriate alcohol of formula (5), which may be commercially available or maybe prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic alcohol or an aromatic alcohol, in each case used together with a metal-hydride base, preferably sodium hydride or potassium hydride. These reactions may be carried out in an ethereal solvent such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably dioxane, optionally containing a co-solvent such as N,N-dimethylformamide, or in the respective alcohol as solvent, at a temperature between room temperature and the reflux temperature of the solvent, preferably about 100xc2x0 C., for 2-72 hours, preferably 16 hours. The product of Formula I, where A is CH2O, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
To prepare the compounds of formula IA or IB, wherein A is xe2x80x94CH2xe2x80x94, the 2-chloro-isonicotinamide intermediate of formula (4A1) or (4B1) is treated with a large excess of an appropriate amine of formula (9), which may be commercially available or may be prepared by methods well known in the art, and which may be chosen from: a primary or secondary aliphatic amine or an aromatic amine. These reactions may be carried out in the absence of added solvent, or optionally in the presence of a solvent such as N,N-dimethylformamide or N-methylpyrrolidone, at an elevated temperature, preferably about 60xc2x0 C., for 2-48 hours, preferably 4 hours. The product of formula I, where A is CH2, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
One method of preparation of compounds of formula IA4 or IB4 and IA5 or IB5 is shown in reaction schemes 9 and 10 below. 
wherein Axe2x80x2xe2x80x94R are together C4-6-cycloalkenyl or dihydropyran and Axe2x80x94R are together C4-6-cycloalkyl or tetrahydropyran. 
wherein Axe2x80x2xe2x80x94R are together C4-6-cycloalkenyl or dihydropyran and Axe2x80x94R are together C4-6-cycloalkyl or tetrahydropyran.
The starting tributylstannane compounds of formula (7) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The compounds of formula IA4 or IB4 are prepared by treating 2-bromo-isonicotinamide intermediates of formula (4A) or 2-bromo-nicotinamide intermediates of formula (4B) with an excess of a tributylstannane compound of formula (7) in an organic solvent, preferably N,N-dimethylformamide, containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride, and in the presence of other additives such as triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-methylphenol. The reaction is carried out at elevated temperature, preferably about 100xc2x0 C., for about 16-96 hours, preferably about 72 hours. The product of formula IA4 or IB4 is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
The starting boronic acid compounds of formula (8) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The compounds of formula IA4 or IB4 may alternatively be prepared by treating 2-bromo-isonicotinamide intermediates of formula (4A) or 2-bromo-nicotinamide intermediates of formula (4B) with an excess of a boronic acid compound of formula (8). The reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(triphenylphosphine)palladium(II) chloride, and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out in the presence of other additives such as triphenylphosphine, lithium chloride and 2,6-di-tert-butyl-4-methylphenol. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 16-96 hours, preferably about 48 hours. The product of formula IA4 or IB4 is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
One method of preparation of compounds of formula IA5 or IB5 is by hydrogenation of a compound of formula IA4 or IB4 in the presence of a hydrogenation catalyst, preferably 10% palladium on charcoal. These reactions may be carried out in a mixture of organic solvents, preferably a mixture of methanol and dichloromethane, at room temperature and at a pressure of one atmosphere or above, preferably at one atmosphere, for 2-48 hours, preferably about 16 hours. The product of formula IA5 or IB5, where A is carbon, is isolated by conventional means, and preferably purified by means of chromatography or recrystallisation.
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Preparations and Examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
The compounds of Formula IA or IB may be basic, for example in cases where the residue Axe2x80x94R contains a basic group such as an aliphatic or aromatic amine moiety. In such cases the compounds of Formula IA or IB may be converted to a corresponding acid addition salt.
The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0xc2x0 C. and 50xc2x0 C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of Formula IA and IB may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The compounds of formulas IA and IB and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are adenosine receptor ligands and possess a high affinity towards the adenosine A2A receptor.
The compounds were investigated in accordance with the test given hereinafter.
The human adenosine A2A receptor was recombinantly expressed in chinese hamster ovary (CHO) cells using the semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenised and again washed by centrifugation. The final washed membrane pellet was suspended in a Tris (50 mM) buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 10 mM MgCl2 (pH 7.4) (buffer A). The [3H]-SCH-583261 (Dionisotti et al., 1997, Br J Pharmacol 121, 353; 1 nM) binding assay was carried out in 96-well plates in the presence of 2.5 xcexcg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and 0.1 U adenosine deaminiase in a final volume of 200 xcexcl of buffer A. Non-specific binding was defined using xainthine amine congener (XAC; 2 xcexcM). Compounds were tested at 10 concentrations from 10 xcexcM-0.3 nM. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for 1 hour at room temperature before centrifugation and then bound ligand determined using a Packard Topcount scintillation counter. IC50 values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
The preferred compounds show a pKi greater than 8.5. In the list below are described some affinity data to the hA2-receptor:
The compounds of formula IA and IB and the pharmaceutically acceptable salts of the compounds of formula IA and IB can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
The compounds of formula IA and IB can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, maskin, agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula IA and IB or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula IA and IB and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention compounds of formula IA and IB as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the adenosine receptor antagonistic activity, such as Alzheimer""s disease, Parkinson""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents and for the production of corresponding medicaments.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson""s disease.
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50xc2x0 C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press.
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.